Note: Descriptions are shown in the official language in which they were submitted.
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WO 2004/078166 PCT/EP2004/050238
Use of Omega-3-Fatty Acids in the Treatment of Diabetic Patients
DESCRIPTION
This invention concerns the use of a pharmaceutical composition containing
essential
fatty acid ethyl esters originating from fish oils, in particular as a high
concentration
mixture of ethyl esters of (20:5w 3) eicosapentaenoic acid (EPA) and (22:6w
3) docosahexaenoic acid (DHA) in patients who suffer from diabetes.
It is well known that certain essential fatty acids confiained in fish oil
have a fiherapeutic
effect in the prevention and treatment of cardiovascular disorders, such as in
the treat-
ment of hypertension, thrombosis, hypercholesterolemia, arteriosclerosis,
cerebral in-
farction, prevention of sudden death in post myocardial infarction patients,
improve-
ment of endothelial function and hyperlipedemias.
US Patents US 5,502,077, US 5,656,667 and US 5,698,594 can be quoted as exam-
ples. The prevention of cardiovascular events, especially of mortality in
patients who
have survived the hospitalization phase of acute myocardial infarction (ARdll)
is de-
scribed in the international patent application'JVO 00/48592.
The above prior art in particular provide knowledge about the utility of fatty
acids be-
longing to the cal-3 family, more specifically (20:5w 3) eicosapentaenoic acid
(EPA) and
(22:6t~J 3) docosahexaenoic acid (DNA), in treating the above-mentioned
disorders.
The fatty acid EPA, being a precursor of PG13 and TxA3, exerts a preventing
platelet
aggregation effect and an antithombotic effect that can be ascribed to
inhibition of
cyclooxygenase (similar effect to that of aspirin) andlor to competition with
arachidonic
acid for this enzyme, with consequent reduction in the sythesis of PGE2 and
TxA2,
which are well known platelet aggregating agents.
On the other hand the fatty acid DHA is the most important component of
cerebral lip-
ids in man and furthermore, being a structural component of the platelet cell
it inter-
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WO 2004/078166 PCT/EP2004/050238
venes indirectly in increasing platelet fluidity, thus playing an important
role in an-
tithombotic activity.
The international patent application WO 89/11521, whose description is herein
incorpo-
rated by reference, describes in particular an industrial process for
extracting mixtures
with a high content in poly-unsaturated acids, including EPA and DHA and their
ethyl
esters, from animal andlor vegetable oils.
Mixtures of fatty acids, especially EPA/DHA, obtained according to WO
89/11521, are
reported to be particularly useful in the treatment of cardiovascular
diseases.
However, current methods of treatment used in human therapy have been shown to
be
insufficient in patients who have a diabetes mellitus, in particular in those
patients in
whom it is desired to also prevent cardiovascular events. It is well known
that patients
with diabetes, in particular with diabetes mellitus, are at a substantially
increased risk
of cardiovascular events and death.
Therefore, there still is a substantial need for improved and effective
treatments with
drugs, in particular for preventing these recurrences. Object of this
invention, therefore,
is to provide such improved and effective treatment of diabetic patients.
This invention, therefore, suggests the novel use of essential fatty acids
with a high
content in EPA-ethyl ester or DHA-ethyl ester or a high concentration mixture
thereof,
in the preparation of a medicament useful for the treatment of patients
suffering from
diabetes. In particular, the invention is directed to preventing
cardiovascular events in
patients who have diabetes mellitus.
For ease of description "EPA-ethyl ester and "DHA-ethyl ester" will be also
quoted
here as °'EPA" and "DHA".
In particular this invention pertains to the use of essential fatty acids
containing a mix-
ture of eicosapentanoic acid ethyl ester (EPA) and docosahexaenoic acid ethyl
ester
(DNA) in the preparation of a medicament useful for the treatment of patients
suffering
from diabetes, preferably for preventing cardiovascular events in patienfis
who have
diabetes, where the content in EPA and DHA in such mixture is greater than 25%
b.w.
An essential fatty acid with high content in EPA or DHA, according to the
present in-
vention, preferably contains more than 25°!° by weight (b.w.),
in particular from about
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3
60 to about 100% of such ester. These compounds can be obtained by known meth-
ods.
In an essential fatty acid with a high concentration mixture of EPA and DHA,
preferably
such mixture has a content in EPA and DHA greater than 25% by weight, in
particular
from about 30 to about 100% by weight, preferably about 85% by weight.
In the EPA/DHA mixture, EPA preferably is present in a percentage from about
40 to
60% by weight and DHA, preferably in a percentage from about 25 to about 45-
50%.
In any case the preferred EPA/DHA ratio in such EPAIDHA mixture is about
0.9/1.5.
PHARMAC~L~~Y
Diabetes mellitus has become an increasingly prevalent disease worldwide. The
preva-
lence of diabetes is increasing rapidly and the number of individuals with
type II diabe-
tes (80-90% of all diabetic people) is depicted to reach 300 million in the
year 2025,
accounting for 5.4% of the global population. Furthermore, cardiovascular
events are
important contributors to morbidity and mortality in patients with diabetic
disease. The
risk of death from cardiovascular disease is in patients with diabetes two to
six times
that among persons without diabetes. Currently, over 50% of diabetic patients
die from
coronary heart disease. In contrast to non-diabetic people, coronary heart
mortality has
not declined in diabetic people. Type II diabetes eliminates the protective
advantage of
female sex against coronary heart disease mortality. The prognosis after a
coronary
heart disease event is poorer in diabetic people than in non-diabetic people.
V9lithin 1
year after an acute myocardial infarction, 44..2% of type II diabetic men and
38.9% of
type II diabetic women die.
All manifestations of coronary heart disease are at least twice as common in
pafiients
with diabetes as in non diabetic individuals. Moreover, recently close
interrelations be-
tween diabetes and cardiovascular disease, not at least with coronary artery
disease,
were elucidated. It has been demonstrated in a number of studies that 28% of
patients
with known coronary artery disease have diabetes, and as many as 70% of
patients
with acute coronary syndromes have abnormal glucose metabolism, either in the
form
of diabetes or impaired glucose tolerance. Major risk factors for coronary
heart disease
in patients with diabetes are:
1. unfavorable lipoprotein profile, characterized by increased serum
triglycerides;
2. elevated blood pressure;
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4
3. predisposition to formation of thrombosis, including the following
manifestations:
high concentrations of plasminogen activator-1 and cytokines;
4. impairment of endothelia-dependent vasodilatation;
5. cardiac autonomic impairment leading to decreased ischaemic pain
perception,
higher heart rate and decresed heart rate variability, which in turn increases
the
risk for sudden death.
The efficacy of the treatment, according to the present invention, is proven
by ample
pre-clinical and clinical evidence:
1. EPA plus DHA induces a reduction in the levels of triglycerides and of very-
low
density lipoprotein cholesterol (VLDL) in patients with hypertriglyceremia;
2. EPA plus DHA does lower blood pressure in patients with hypertension;
3. Dietary EPA and DHA down-regulate gene expression of platelet-derived
growth
factor-A and of platelet-derived growth factor-B in human mononuclear cells;
4. ~upplemeniation with EPA plus DHA mitigates the course of coronary athero-
sclerosis in patients with coronary heart disease;
5. EPA and DHA improves endothelial function in heart transplant recipients.
ft. Experimental studies have shown that EPA and DHA are antiarrhythmic in sev-
eral animal models, probably due to specific modulation of ion currents;
7. EPA and DHA increases heart rate variability in healthy volunteers and in
survi-
vors of a myocardial infarction;
8. EPA plus DHA decreases the incidence of sudden death in survivors of a myo-
cardial infiarction.
The above mentioned evidence of reducing risk fiactors shows that the present
inven-
tion provides a new and valuable therapeutic tool for treating diabetic
patients, and in
particular for preventing cardiovascular events in diabetic patients.
Accordingly, this invention also provides a method for treating diabetic
patients, pref-
erably patients with diabetes mellitus and in particular for preventing
cardiovascular
events in diabetic patients, preferably in patients with diabetes mellitus,
comprising
administering to such patient a therapeutically effective amount of a
medicament con-
taining essential fatty acids with a high content in EPA-ethyl ester or DHA-
ethyl ester or
a high concentration mixture thereof.
The essential fatty acids, according to the invention, can either have a high
content, for
instance more than 25% b.w., in EPA or DHA or in a mixture thereof. However,
EPA
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and DHA-ethyl ester are preferably present as a mixture thereof with a content
in EPA
and DHA higher than 25% b.w., in particular from about 30 to about 100% b.w.,
pref-
erably about 85% b.w.
Based on the available evidence, according to a preferred aspect of the
invention, the
dosage of an essential fatty acid containing an EPA and DHA mixture with 85%
b.w.
titer for oral administration to a patient may vary from about 0.7g to about
6g daily,
preferably about 1g daily.
This amount of product as EPA and DHA mixture (or amount of EPA alone or DHA
alone) may be administered in several divided doses throughout the day or
preferably
in a single administration, in order to achieve the desired hematic level.
Obviously it is
at the discretion of the physician to adjust the quantity of product to be
administered
according to the age, weight and general conditions of the patient.
The medicament, e.g. in the form of a pharmaceutical composition, according to
this
invention can be prepared according to known methods in the art. The preferred
route
of administration is the oral one, however leaving alternative routes of
administration,
such as the parenteral route, to the discretion of the physician.
The preferred variants of the present invention are furthermore defined in the
sub-
claims.
The f~Ilowing examples illustrate preferred formulations for oral
administration, but do
not intend to limit the invention in any way.
Gelatin capsules
According to known pharmaceutical techniques, capsules having the composition
be-
low and containing 1g of active ingredient (EPA and DHA, 85% titer) per
capsule are
prepared.
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6
Formulation 1
EPA-ethyl 525 mg !
ester capsule
DHA-ethyl 315 mg I
ester capsule
d-alphatocopherol41U !capsule
gelatin 246 mg l
capsule
glycerol 118 mg I
capsule
red iron 2.27 mg
oxide / capsule
yellow iron 1.27 mg
oxide / capsule
Formulation 2
Ethyl esters of polyunsaturated1000
fatty acids mg
with content in ethyl
esters of w-3 poly-
unsaturated esters (eicosapentaenoic
EPA,
docosahexaenoic DHA) 850
mg
d-1-a-tocopherol 0.3
mg
gelatin succinate 233
mg
glycerol 67
mg
sodium p-oxybenzoate 1.09
mg
sodium propyl p-oxobenzoate0.54
mg
